Severe neonatal subgaleal hemorrhage as the first presentation of hemophilia A.
Subgaleal hemorrhage is a rare but potentially fatal birth trauma. It is caused by rupture of the emissary veins (connections between the dural sinuses and scalp veins), followed by the accumulation of blood between the epicranial aponeurosis and the periosteum. Usually, it is associated with instrumental delivery (vacuum extraction, forceps delivery), but it may also occur spontaneously, suggesting the possibility of congenital bleeding disorder. A full term male neonate was born at 40 weeks gestation by spontaneous vaginal delivery, with birth weight of 3,700 g. The Apgar scores were 9 and 10 at 1 and 5 minutes, respectively. At the age of 23 hours, the baby became pale and lethargic. Large fluctuant swelling on his head was noted. He developed severe anemia and hypovolemia as a result of massive subgaleal hemorrhage. After successful treatment, the baby fully recovered. Follow-up and further evaluation revealed hemophilia A as a result of a de novo mutation. This case illustrates that subgaleal hemorrhage may be the first presentation of hemophilia A. Infants without obvious risk factors for developing subgaleal hemorrhage should be evaluated for congenital bleeding disorder. Successful outcome in affected infants requires early diagnosis, careful monitoring and prompt treatment.


Pseudomonas aeruginosa in cystic fibrosis patients with G551D-CFTR treated with ivacaftor.
Ivacaftor improves outcomes in cystic fibrosis (CF) patients with the G551D mutation; however, effects on respiratory microbiology are largely unknown. This study examines changes in CF respiratory pathogens with ivacaftor and correlates them with baseline characteristics and clinical response. The G551D Observational Study enrolled a longitudinal observational cohort of US patients with CF aged 6 years and older with at least 1 copy of the G551D mutation. Results were linked with retrospective and prospective culture data in the US Cystic Fibrosis Foundation's National Patient Registry. Pseudomonas aeruginosa infection category in the year before and year after ivacaftor was compared and correlated with clinical findings. Among 151 participants prescribed ivacaftor, 29% (26/89) who were culture positive for P. aeruginosa the year prior to ivacaftor use were culture negative the year following treatment; 88% (52/59) of those P. aeruginosa free remained uninfected. The odds of P. aeruginosa positivity in the year after ivacaftor compared with the year prior were reduced by 35% (odds ratio [OR], 0.65; P < .001). Ivacaftor was also associated with reduced odds of mucoid P. aeruginosa (OR, 0.77; P = .013) and Aspergillus (OR, 0.47; P = .039), but not Staphylococcus aureus or other common CF pathogens. Patients with intermittent culture positivity and higher forced expiratory volume in 1 second (FEV1) were most likely to turn culture negative. Reduction in P. aeruginosa was not associated with change in FEV1, body mass index, or hospitalizations. Pseudomonas aeruginosa culture positivity was significantly reduced following ivacaftor treatment. Efficacious CFTR modulation may contribute to lower frequency of culture positivity for P. aeruginosa and other respiratory pathogens, particularly in patients with less established disease.


Investigation of different stimulation patterns with doublet pulses to reduce muscle fatigue.
Introduction: Functional electrical stimulation is a common technique used in the rehabilitation of individuals with a spinal cord injury to produce functional movement of paralysed muscles. However, it is often associated with rapid muscle fatigue which limits its applications. Methods: The objective of this study is to investigate the effects on the onset of fatigue of different multi-electrode patterns of stimulation via multiple pairs of electrodes using doublet pulses: Synchronous stimulation is compared to asynchronous stimulation patterns which are activated sequentially (AsynS) or randomly (AsynR), mimicking voluntary muscle activation by targeting different motor units. We investigated these three different approaches by applying stimulation to the gastrocnemius muscle repeatedly for 10 min (300 ms stimulation followed by 700 ms of no-stimulation) with 40 Hz effective frequency for all protocols and doublet pulses with an inter-pulse-interval of 6 ms. Eleven able-bodied volunteers (28 ± 3 years old) participated in this study. Ultrasound videos were recorded during stimulation to allow evaluation of changes in muscle morphology. The main fatigue indicators we focused on were the normalised fatigue index, fatigue time interval and pre-post twitch-tetanus ratio. Results: The results demonstrate that asynchronous stimulation with doublet pulses gives a higher normalised fatigue index (0.80 ± 0.08 and 0.87 ± 0.08) for AsynS and AsynR, respectively, than synchronous stimulation (0.62 ± 0.06). Furthermore, a longer fatigue time interval for AsynS (302.2 ± 230.9 s) and AsynR (384.4 ± 279.0 s) compared to synchronous stimulation (68.0 ± 30.5 s) indicates that fatigue occurs later during asynchronous stimulation; however, this was only found to be statistically significant for one of two methods used to calculate the group mean. Although no significant difference was found in pre-post twitch-tetanus ratio, there was a trend towards these effects. Conclusion: In this study, we proposed an asynchronous stimulation pattern for the application of functional electrical stimulation and investigated its suitability for reducing muscle fatigue compared to previous methods. The results show that asynchronous multi-electrode stimulation patterns with doublet pulses may improve fatigue resistance in functional electrical stimulation applications in some conditions.


Active destabilization of base pairs by a DNA glycosylase wedge initiates damage recognition.
Formamidopyrimidine-DNA glycosylase (Fpg) excises 8-oxoguanine (oxoG) from DNA but ignores normal guanine. We combined molecular dynamics simulation and stopped-flow kinetics with fluorescence detection to track the events in the recognition of oxoG by Fpg and its mutants with a key phenylalanine residue, which intercalates next to the damaged base, changed to either alanine (F110A) or fluorescent reporter tryptophan (F110W). Guanine was sampled by Fpg, as evident from the F110W stopped-flow traces, but less extensively than oxoG. The wedgeless F110A enzyme could bend DNA but failed to proceed further in oxoG recognition. Modeling of the base eversion with energy decomposition suggested that the wedge destabilizes the intrahelical base primarily through buckling both surrounding base pairs. Replacement of oxoG with abasic (AP) site rescued the activity, and calculations suggested that wedge insertion is not required for AP site destabilization and eversion. Our results suggest that Fpg, and possibly other DNA glycosylases, convert part of the binding energy into active destabilization of their substrates, using the energy differences between normal and damaged bases for fast substrate discrimination.


Considerations for Pursuing Multiple Session Forensic Interviews in Child Sexual Abuse Investigations.
Multiple session forensic interviews (MSFI) are a useful tool in the field of child sexual abuse forensic interviewing given the complexity of disclosures and the variety of child-centered needs observed in practice. This paper focuses on the Children's Advocacy Centers of Texas (CACTX) model for conducting MSFIs, illustrated by a description of the statewide training models offered to member centers and enumeration of the MSFI protocol guidelines implemented by one center. A brief history and review of the single session forensic interview (SSFI) is provided followed by considerations for MSFIs in order to establish the development of current and new practices. Clarification of terms are outlined with examples of cases to distinguish between multiple sessions and subsequent sessions. The MSFI guidelines presented demonstrate how an MSFI can fit with the SSFI model.


Diphenhydramine-induced acute dystonia.
A 45-year-old woman was administered oral and intravenous diphenhydramine 25 mg for the treatment of an allergic reaction. Within 2 minutes she rapidly developed trismus, dysarthria, tremors of the upper extremities, left-sided weakness, and diminished consciousness. She was treated with intravenous diazepam and benztropine with good response. After approximately 12 hours the patient's condition was completely resolved except for minor subjective weakness of her left extremities. Her hospital stay was uneventful, and she was discharged after 4 days after refusing rechallenge with the drug. Several cases of acute dystonic reactions secondary to antihistamines have been reported in the literature, four of which involved diphenhydramine. Such reactions may occur after short- or long-term therapy. Most patients experienced rapidly developing trismus, facial dystonia, dysarthria, and occasionally, decreases in consciousness, motor incoordination, and weakness. Because of the widespread availability of diphenhydramine and other antihistamines to the general public, awareness of this effect is of great importance.


Nuclear retention of the lncRNA SNHG1 by doxorubicin attenuates hnRNPC-p53 protein interactions.
The protein p53 plays a crucial role in the regulation of cellular responses to diverse stresses. Thus, a major priority in cell biology is to define the mechanisms that regulate p53 activity in response to stresses or maintain it at basal levels under normal conditions. Moreover, further investigation is required to establish whether RNA participates in regulating p53's interaction with other proteins. Here, by conducting systematic experiments, we discovered a p53 interactor-hnRNPC-that directly binds to p53, destabilizes it, and prevents its activation under normal conditions. Upon doxorubicin treatment, the lncRNA SNHG1 is retained in the nucleus through its binding with nucleolin and it competes with p53 for hnRNPC binding, which upregulates p53 levels and promotes p53-dependent apoptosis by impairing hnRNPC regulation of p53 activity. Our results indicate that a balance between lncRNA SNHG1 and hnRNPC regulates p53 activity and p53-dependent apoptosis upon doxorubicin treatment, and further indicate that a change in lncRNA subcellular localization under specific circumstances is biologically significant.


Spirometry values for detecting a restrictive pattern in occupational health settings.
Pulmonary function tests are valuable measures for diagnosis and management of respiratory diseases. In the field of occupational medicine, spirometry is commonly performed, and in a considerable number of spirometries during occupational health evaluations, restrictive pattern is observed without any respiratory symptoms and may necessitate referral of the subject for body plethysmography, which is an expensive test. In this study, we evaluated the diagnostic accuracy of spirometry for detection of restrictive lung pattern in an occupational setting. In a cross-sectional study from 2008 to 2012, 1224 subjects were selected and entered in the study out of 1,486 individuals referred for annual spirometry. Selected subjects underwent spirometry and body plethysmography. Subjects were divided into two groups of restrictive and non-restrictive patterns and then sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of spirometry for detection of restrictive lung pattern were calculated using total lung capacity measured by plethysmography as the gold standard. Receiver operating characteristic (ROC) curves were used as well. Spirometry showed sensitivity, specificity, PPV and NPV of 97.75%, 73.04%, 73.72% and 97.67% for FVC< lower limit of normal (LLN) and 98.68%, 78.00%, 77.31% and 98.83% for FVC< LLN along with FEV1/FVC≥ LLN, respectively. According to the ROC curve, the best cut-off point for FVC for detection of restrictive lung pattern was 70%. This study showed that spirometry is a useful method in occupational health evaluations to rule out restrictive lung patterns with acceptable accuracy; however, it is not an accurate tool for detection of restrictive lung pattern in an occupational setting. Simultaneous use of FVC and FEV1/FVC for detection of restriction increases the predictive value of spirometry.


A video protocol for rapid dissection of mouse dorsal root ganglia from defined spinal levels.
Dorsal root ganglia (DRG) are heterogeneous assemblies of assorted sensory neuron cell bodies found in bilateral pairs at every level of the spinal column. Pseudounipolar afferent neurons convert external stimuli from the environment into electrical signals that are retrogradely transmitted to the spinal cord dorsal horn. To do this, they extend single axons from their DRG-resident somas that then bifurcate and project both centrally and distally. DRG can be dissected from mice at embryonic stages and any age post-natally, and have been extensively used to study sensory neuron development and function, response to injury, and pathological processes in acquired and genetic diseases. We have previously published a step-by-step dissection method for the rapid isolation of post-natal mouse DRG. Here, the objective is to extend the protocol by providing training videos that showcase the dissection in fine detail and permit the extraction of ganglia from defined spinal levels. By following this method, the reader will be able to swiftly and accurately isolate specific lumbar, thoracic, and cervical DRG from mice. Dissected ganglia can then be used for RNA/protein analyses, subjected to immunohistochemical examination, and cultured as explants or dissociated primary neurons, for in-depth investigations of sensory neuron biology.


Long-term growth and development in children after home parental nutrition.
Growth and development after the cessation of prolonged parenteral nutrition (PN) has not been fully evaluated. Growth, body composition, and nutritional and developmental status were documented in nine children (five boys, four girls) 2 to 6 years old (mean 4.9 +/- 1.0 years) who had previously received long-term PN (mean 14.6 +/- 11.4 months). PN had been discontinued in all subjects for at least 6 months (mean 3.4 +/- 1.4 years); they were receiving oral feedings only. One subject had a significantly low height-for-age, and another had a low percent ideal body weight; five subjects had low total body fat. Serum vitamin A was low in six subjects. Seventy-two-hour fecal fat analysis was abnormal in two of eight subjects. Abnormal bone mineral density was present in four of nine subjects. Psychomotor development was normal in all nine subjects. Two had functional difficulties in swallowing. One or more abnormalities were present in all nine subjects. These findings suggest that children who require prolonged PN in early life are at risk for abnormalities in growth and nutritional status in later childhood; they require long-term dietary, growth, and nutritional monitoring.


[A quantitative determination of IgG anti-D subclasses by Elisa in hemolytic disease of the newborn].
The quantification of IgG anti-D subclasses is one of the most important parameters considered in the assessment of the severity of hemolytic disease of the newborn. Traditionally IgG subclassing is performed using qualitative haemagglutination methods, difficult to interpret. A quantitative enzyme-linked immunosorbent assay (Elisa) was implemented for measuring IgG anti-D subclasses in 20 sera collected from 14 RhD-immunized pregnant women. All 4 IgG subclasses were detected in the 20 sera tested. The mean proportion of IgG1 was 52.8%. The mean proportion of IgG3 was 30.7%. The mean proportions of IgG2 and IgG4 were 14.5 and 1.9% respectively. A good correlation between the sum of IgG subclasses and the severity of HDN was found. Severe HDN occurred when both IgG1 and IgG3 were present. IgG1 anti-D was the predominant subclass in 4 of the 8 severe cases.


Response of keloid fibroblasts to Vitamin D3 and quercetin treatment - in vitro study.
Keloid scars continue to pose a challenge to clinicians as the treatment armamentarium lacks a formidable agent to tackle them. We have undertaken an in vitro study based on the mechanism of action of Vitamin D3 and quercetin on isolated keloid fibroblasts. Dose-dependent action on the reduction of cellular proliferation, collagen synthesis and induction of apoptosis by Vitamin D3 and quercetin are analyzed and probable mechanism of action is elaborated. This study thus opens up newer avenues in tackling keloid scars effectively.


[Ultrasound measurement of fetal head and body sizes in the assessment of fetal growth].
The growth of the ultrasound biparietal diameter (BPD), head circumference (HC), chest circumference (CC) and abdominal circumference (AC) during normal pregnancy is presented. A total of 799 measurements of 619 pregnant women from 20 to 42 weeks gestation were taken. 1) The correlation coefficient between gestational weeks and BPD, HC, CC, AC was 0.901, 0.972, 0.990, 0.988 respectively. 2) The correlation of HC, CC and AC was HC greater than AC greater than CC before 35 weeks but after 35 weeks it was AC greater than HC greater than CC. 3) The growth of large-for-date fetuses (LFD) was more rapid than that of appropriate-for-date fetuses (AFD). It was difficult to detect LFD before 30 weeks. 4) In the group of small-for-date fetuses, the HC/AC ratio was always greater than one. It was suggested that the growth of the fetal body was slower than that of the head.


Leucokinin mimetic elicits aversive behavior in mosquito Aedes aegypti (L.) and inhibits the sugar taste neuron.
Insect kinins (leucokinins) are multifunctional peptides acting as neurohormones and neurotransmitters. In females of the mosquito vector Aedes aegypti (L.), aedeskinins are known to stimulate fluid secretion from the renal organs (Malpighian tubules) and hindgut contractions by activating a G protein-coupled kinin receptor designated "Aedae-KR." We used protease-resistant kinin analogs 1728, 1729, and 1460 to evaluate their effects on sucrose perception and feeding behavior. In no-choice feeding bioassays (capillary feeder and plate assays), the analog 1728, which contains α-amino isobutyric acid, inhibited females from feeding on sucrose. It further induced quick fly-away or walk-away behavior following contact with the tarsi and the mouthparts. Electrophysiological recordings from single long labellar sensilla of the proboscis demonstrated that mixing the analog 1728 at 1 mM with sucrose almost completely inhibited the detection of sucrose. Aedae-KR was immunolocalized in contact chemosensory neurons in prothoracic tarsi and in sensory neurons and accessory cells of long labellar sensilla in the distal labellum. Silencing Aedae-KR by RNAi significantly reduced gene expression and eliminated the feeding-aversion behavior resulting from contact with the analog 1728, thus directly implicating the Aedae-KR in the aversion response. To our knowledge, this is the first report that kinin analogs modulate sucrose perception in any insect. The aversion to feeding elicited by analog 1728 suggests that synthetic molecules targeting the mosquito Aedae-KR in the labellum and tarsi should be investigated for the potential to discover novel feeding deterrents of mosquito vectors.


Copper(II) and the pathological H50Q α-synuclein mutant: Environment meets genetics.
Copper is one of the metals described to bind the Parkinson disease-related protein α-synuclein (aSyn), and to promote its aggregation. Although histidine at position 50 in the aSyn sequence is one of the most studied copper-anchoring sites, its precise role in copper binding and aSyn aggregation is still unclear. Previous studies suggested that this residue does not significantly affect copper-mediated aSyn aggregation. However, our findings showed that the aggregation of the pathological H50Q aSyn mutant is enhanced by copper hints otherwise. Despite the inexistence of a model for aSyn H50Q-copper complexation, we discuss possible mechanisms by which this metal contributes to the misfolding and self-assembly of this particular aSyn mutant. Considering the genetic association of the H50Q mutation with familial forms of Parkinson disease, and the fact that copper homeostasis is deregulated in this disorder, understanding the interplay between both factors will shed light into the molecular and cellular mechanisms triggering the development and spreading of the aSyn pathology.


Qdot nanocrystal conjugates conjugated to bombesin or ANG II label the cognate G protein-coupled receptor in living cells.
Quantum dots (Qdot Nanocrystal Conjugates; Quantum Dot, Hayward, CA) exhibit high fluorescence and low photobleaching compared with organic dyes, properties that should enhance their detection at low densities. In view of the properties of Qdots and the biological and pharmaceutical importance of G protein-coupled receptors (GPCRs), we attempted to use Qdots to label GPCRs in a variety of live cell types. An agonist consisting of biotinylated bombesin or ANG II was conjugated to Qdot Nanocrystal Conjugates coated with streptavidin through a biotin-streptavidin linkage (Qdot agonist). Herein we demonstrate that Qdot-bombesin conjugate can label the bombesin-preferring GPCR in living mouse Swiss 3T3 cells and in Rat-1 cells. Similarly, we used the Qdot-ANG II conjugate to label GPCR in intact rat intestinal epithelial cells (IEC)-18 and in a human pancreatic adenocarcinoma cell line of ductal origin, HPAF-II cells. We demonstrate that Qdot-ANG II is brighter and more photostable than agonist labeled with the organic dye Cy3. Our results demonstrate that Qdot technology can be adapted to monitor ligand binding to GPCRs. Combined with the narrow and symmetric emission profile of Qdot Nanocrystal Conjugates, this information suggests the potential for a new multiplex strategy to determine the effect of agonists and/or antagonists on agonist binding to several GPCRs simultaneously in living cells.


[Establishment of segregating inbred strain of Yuyi hairless mice and its monitoring of genetic characteristics].
Using brother-sister inbreeding with forced heterozygosity to breed a new segregating inbred strain which carry mutant hairless gene. Then, genetic monitoring was conducted by the skin grafting test, coat color test and biochemical marker analysis, and its basic biological characteristics were studied with corresponding methods. The Results are that the Yuyi Hairless Mice (YYHL) with unique biological characteristics have been bred successfully and have progressed to 30th generation since 1991. Thirteen biochemical markers loci on nine chromosomes coding biochemical markers measured with electrophoresis were all homogenous. The skin grafting test showed that no dropping graft was found during 100 days after transplanting, implying the YYHL was of isohistogeneicity. Analysis of coat color genes indicated that the hair color of first generation hybrid crossed between YYHL and DBA/2 was all agouti suggesting that the coat color genes of the YYHL were homogenous. The gene type is AABBccDD. All these showed that the YYHL have been an inbred strain reaching the international standards.


Assessment of GSK1904529A as a promising anti-osteosarcoma agent.
The insulin growth factor-I receptor (IGF1R) signaling is a key mechanism for osteosarcoma (OS) cell proliferation. GSK1904529A is a novel small molecule IGF1R kinase inhibitor. Its activity against OS cells was tested. In both established OS cell lines (Saos-2 and MG-63) and primary human OS cells, treatment with GSK1904529A (at nM concentrations) significantly inhibited cell proliferation. At the molecular level, GSK1904529A almost completely blocked IGF1R activation in OS cells, and inhibited downstream AKT-ERK activation. IGF1R silence by targeted shRNA also inhibited AKT-ERK activation and Saos-2 cell proliferation. Significantly, GSK1904529A was unable to further inhibit proliferation of IGF1R-silenced Saos-2 cells. In vivo, GSK1904529A administration orally inhibited Saos-2 tumor growth in nude mice. Together, these results suggest that targeting IGF1R by GSK1904529A inhibits OS cell growth in vitro and in vivo.


Mo(W)/Cu/S cluster-based supramolecular arrays assembled from preformed clusters [Et4N]4[WS4Cu4I6] and [(n-Bu)4N]2[MoOS3Cu3X3] (X = I, SCN) with flexible ditopic ligands.
In our working toward the rational design and synthesis of cluster-based supramolecular architectures, a set of new [WS4Cu4]- or [MoOS3Cu3]-based supramolecular assemblies have been prepared from reactions of preformed cluster compounds [Et4N]4[WS4Cu4I6] (1) and [(n-Bu)4N]2[MoOS3Cu3X3] (2, X = I; 3, X = SCN) with flexible ditopic ligands such as dipyridylsulfide (dps), dipyridyl disulfide (dpds), and their combinations with dicyanamide (dca) anion and 4,4'-bipy. The cluster precursor 1 reacted with dps or dpds and sodium dicyanamide (dca) in MeCN to produce [WS4Cu4I2(dps)3].2MeCN (4.2MeCN) and [WS4Cu4(dca)2(dpds)2].Et2O.2MeCN (5.Et2O.2MeCN), respectively. On the other hand, treatment of 2 with dpds in DMF/MeCN afforded [MoOS3Cu3I(dpds)2].0.5DMF.2(MeCN)0.5 (6.0.5DMF.2(MeCN)0.5) while reaction of 3 with sodium dicyanamide (dca) and 4,4'-bipy in DMF/MeCN gave rise to [MoOS3Cu3(dca)(4,4'-bipy)1.5].DMF.MeCN (7.DMF.MeCN). Compounds 4.2MeCN, 5.Et2O.2MeCN, 6.0.5DMF.2(MeCN)0.5, and 7.DMF.MeCN have been characterized by elemental analysis, IR spectroscopy, and single-crystal X-ray crystallography. Compound 4 contains a 2D layer array made of the saddle-shaped [WS4Cu4] cores interlinked by three pairs of Cu-dps-Cu bridges. Compound 5 has another 2D layer structure in which the [WS4Cu4] cores are held together by four pairs of Cu-dca-Cu and Cu-dpds-Cu bridges. Compound 6 displays a 1D spiral chain structure built of the nido-like [MoOS3Cu3] cores via two pairs of Cu-dpds-Cu bridges. Compound 7 consists of a 2D staircase network in which each [MoOS3Cu3(4,4'-bipy]2 dimeric unit interconnects with four other equivalent units by a pair of 4,4'-bipy ligands and two pairs of dca anions. The [WS4Cu4] core in 4 or 5 and the [MoS3Cu3] core in 7 show a planar 4-connecting node and a seesaw-shaped 4-connecting node, respectively, which are unprecedented in cluster-based supramolecular compounds. The successful assembly of 4-7 from the three cluster precursors 1-3 through flexible ditopic ligands provides new routes to the rational design and construction of complicated cluster-based supramolecular arrays.


Could Intelligent Speed Adaptation make overtaking unsafe?
This driving simulator study investigated how mandatory and voluntary ISA might affect a driver's overtaking decisions on rural roads, by presenting drivers with a variety of overtaking scenarios designed to evaluate both the frequency and safety of the manoeuvres. In half the overtaking scenarios, ISA was active and in the remainder ISA was switched off. A rural road was modelled with a number of 2+1 road sections, thus allowing drivers a protected overtaking opportunity. The results indicate that drivers became less inclined to initiate an overtaking manoeuvre when the mandatory ISA was active and this was particularly so when the overtaking opportunity was short. In addition to this, when ISA was activated drivers were more likely to have to abandon an overtaking, presumably due to running out of road. They also spent more time in the critical hatched area-a potentially unsafe behaviour. The quality of the overtaking manoeuvre was also affected when mandatory ISA was active, with drivers pulling out and cutting back in more sharply. In contrast, when driving with a voluntary ISA, overtaking behaviour remained mostly unchanged: drivers disengaged the function in approximately 70% of overtaking scenarios. The results of this study suggest that mandatory ISA could affect the safety of overtaking manoeuvres unless coupled with an adaptation period or other driver support functions that support safe overtaking.


Mothers, daughters and dieting: investigating the transmission of weight control.
Research by Pike & Rodin (1991) found higher levels of weight concern and dissatisfaction with family functioning in mothers of eating disordered adolescent girls. The present study sought to extend this research by examining the maternal influences on weight and dieting concerns at a younger age. A cross-sectional comparison of high and low dietary restraint girls and their mothers was used. Two groups of 20 11-year-old girls and their mothers completed assessments of dietary restraint, body shape preference, self-perception, family functioning and body weight and height. Mothers of high restraint girls did not differ from comparison mothers in their current level of dieting, but did report more between-meal snacking and fasting. In addition, they rated their daughters' attractiveness significantly lower than the other mothers. Furthermore, families with a highly restrained daughter scored significantly lower on perceived family cohesion, organization and moral-religious emphasis. The parallel with the findings of Pike & Rodin supports the role that mothers may play in the transmission of cultural values regarding weight, shape and appearance. Importantly, it also places early dieting within a wider context of dissatisfaction with family functioning.


Glabellar pomade crust mimicking dyskeratosis follicularis.
A 79-year-old female patient presented with a slowly developing crusting, itching verrucous lesion of the forehead of 3 months' duration. She had no personal or family history of skin disease. On examination she presented with a hyperpigmented plaque of the glabellar region that resembled dyskeratosis follicularis Darier. A detailed medical history was taken and a skin biopsy was performed. Epidermal acanthosis and enlargement of follicle ostia with foreign material were found. The patient reported use of an ointment twice daily. She had a single cosmetic treatment where powder of unspecified composition had been used. The diagnosis of pomade crust was confirmed. Follicular material was enucleated mechanically and the area was treated with a metronidazole cream. The lesions completely disappeared.


Pharmacokinetics and safety study of posaconazole intravenous solution administered peripherally to healthy subjects.
This study evaluated the safety, tolerability, and pharmacokinetics of a posaconazole i.v. (intravenous) solution. This was a single-center, 2-part, randomized, rising single- and multiple-dose study in healthy adults. In part 1, subjects received 0 (vehicle), 50, 100, 200, 250, or 300 mg posaconazole in a single dose i.v. by 30-min peripheral infusion (6 cohorts of 12 subjects each [9 active and 3 placebo], making a total of 72 subjects). Blood samples were collected until 168 h postdose. In part 2, subjects were to receive 2 peripheral infusions at a 12-h interval on day 1 followed by once-daily infusion for 9 days. However, part 2 was terminated early because of high rates of infusion site reactions with multiple dosing at the same infusion site. The pharmacokinetics results for part 1 (n=45 subjects) showed that the mean posaconazole exposure (area under the concentration-time curve from time zero to infinity [AUC0-∞]) ranged from 4,890 to 46,400 ng · h/ml (range of coefficient of variation values, 26 to 50). The dose-proportionality slope estimate (90% confidence interval) for AUC0-∞ was 1.30 (1.19 to 1.41), indicating a greater-than-dose-proportional increase. The data for safety in part 1 show that 29/72 subjects had ≥1 adverse event. Infusion site reactions were reported in 2/9 vehicle subjects, 0/18 placebo subjects, and 7/45 i.v. posaconazole subjects. The data for safety in part 2 show that infusion site reactions were reported in 1/4 (25%) placebo subjects, 3/9 (33%) vehicle control subjects, and 4/5 (80%) i.v. posaconazole (100 mg) subjects (3 posaconazole recipients subsequently developed thrombophlebitis and were discontinued from treatment). In conclusion, the posaconazole i.v. solution showed a greater-than-dose-proportional increase in exposure, primarily at doses below 200 mg. When administered peripherally at the same infusion site, multiple dosing of i.v. posaconazole led to unacceptably high rates of infusion site reactions. Intravenous posaconazole was otherwise well tolerated. Single doses of i.v. posaconazole were tolerated when given through a peripheral vein over 30 min.


Glycyrrhetinic acid suppressed NF-κB activation in TNF-α-induced hepatocytes.
Tumor necrosis factor-alpha (TNF-α) is a crucial inflammatory cytokine when hepatocytes are damaged. Glycyrrhiza uralensis Fisch. (Chinese licorice) has been widely used in Chinese herbal prescriptions for the treatment of liver diseases and as a food additive. Nuclear factor-kappa B (NF-κB) reporter gene assay in TNF-α-induced HepG2 was used as a screening platform. IκBα phosphorylation and p65 translocation were measured by Western blotting, and nitric oxide (NO) production and inducible nitric oxide synthase (iNOS) gene expression were further confirmed in rat primary hepatocytes. Results showed that TNF-α enhanced NF-κB activity was significantly attenuated by glycyrrhetinic acid in a concentration-dependent manner in the NF-κB reporter gene assay. Glycyrrhetinic acid decreased the gene expression of iNOS through inhibited IκBα phosphorylation and p65 translocation in protein level. Furthermore, NO production and iNOS expression were reduced by glycyrrhetinic acid in TNF-α-induced rat primary hepatocytes. These results suggest that glycyrrhetinic acid may provide hepatoprotection against chronic liver inflammation through attenuating NF-κB activation to alleviate the inflammation.


Performance of primary dental care services: an ecological study in a large Brazilian city.
This study explored the association between area-level primary dental care performance and area-level demographics, dental treatment need, and health care service indicators. An ecological cross-sectional study was performed in Belo Horizonte, Brazil, in 2010. The 142 primary health care (PHC) units were grouped based on the following variables: access to individual dental treatment, frequency of dental emergencies, and frequency of individual preventive procedures. The independent variables analyzed were demographic variables, dental treatment need, and health care service indicators. The data were obtained from the information systems of the Brazilian Ministry of Health and the city of Belo Horizonte. We explored the associations between membership in a specific PHC cluster type and the independent variables using multinomial logistic regression with a significance level of 5%. Variables such as the high/very high vulnerability of population, rate of completed treatment, and rate of referrals of users to secondary care were independently associated with the clusters (P < 0.05). The performance of primary dental care services was associated with patient demographics, dental treatment need, and referrals. The results of this study have implications for the planning of public policies.


The Role of Dapagliflozin in the Management of Heart Failure: An Update on the Emerging Evidence.
The burden and cost of heart failure management, primarily in the form of hospitalization in the setting of decompensated heart failure, continue to be some of the biggest clinical challenges in cardiovascular medicine. In recently published randomized controlled trials, including DAPA-HF, sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin was shown to reduce hospitalization from heart failure or mortality associated with cardiovascular causes, when added to existing guideline-directed medical therapy. The American College of Cardiology (ACC) released a Clinical Pathway guideline that recommends the use of dapagliflozin in clinical management of heart failure, with or without diabetes. Furthermore, the results of the DAPA-CKD trial broaden the utility of dapagliflozin as a therapeutic option in patients with advanced kidney disease. In this article, the authors explore the existing evidence on dapagliflozin in heart failure with reduced ejection fraction and highlight the need for further research on uses of dapagliflozin in the world of heart failure.


[Diagnosis and conservative treatment of acute pyelonephritis in diabetes mellitus].
To raise efficacy of conservative treatment of patients with acute pyelonephritis (AP) which developed in the presence of diabetes mellitus (DM). Elderly patients (n = 218, 182 females and 36 males) with DM and AP enered the study. DM type 1 and 2 were diagnosed in 41 and 177 of them. Pyelonephritis was diffuse-purulent, pyodestructive, calculous, pyocalculous. Conservative treatment was made in 160 patients, surgical treatment--in 58. Lethal outcomes (14 cases) were registered as a rule in patients with bilateral pyodestructive pyelonephritis. AP is a severe complication of DM. The severity of DM decompensation and metabolic disorders is proportional to AP severity. AP in diebetics runs often an asymptomatic course and the diagnosis is difficult. Therapeutic policy is individual with consideration of a clinical course. Positive results were achieved in 80% patients.


Evaluation of the VIDAS glutamate dehydrogenase assay for the detection of Clostridium difficile.
We evaluated the performance of the VIDAS GDH assay for the detection of Clostridium difficile. In total, 350 fecal specimens collected from patients clinically suspected of having CDI were analyzed by C. difficile culture and enzyme-linked fluorescent immunoassay (VIDAS GDH); the results were compared with those of toxigenic C. difficile culture (TC), PCR (Xpert C. difficile assay), and toxin AB EIA (VIDAS CDAB). The numbers of culture-positive and culture-negative samples were 108 and 242, respectively. The concordance between the GDH assay and C. difficile culture was 90.3%. With PCR, 12 more samples were found to be positive in GDH-positive/C. difficile culture-negative specimens. Thus, the concordance between GDH assay and C. difficile culture/PCR was 93.7%. The sensitivity, specificity, positive predictive value, and negative predictive value of the VIDAS GDH assay were 97.2%, 87.2%, 77.2%, and 98.6%, respectively, based on the C. difficile culture, and 97.5%, 91.7%, 86.0%, and 98.6%, respectively, based on C. difficile culture/PCR. Positivity rates of the GDH assay were partially associated with those of semi-quantitative C. difficile cultures, which were maximized in grade 3 (>100 colony-forming unit [CFU]) compared with grade 1 (<10 CFU). We evaluated the two-step or three-step algorithm using GDH assay as a first step. No toxin EIA-positive case was found among GDH-negative samples, and 60.8% (48/79) were TC- and/or PCR-positive among the GDH-positive/toxin EIA-negative samples. Thus, approximately 25% of the 350 samples required a confirmatory test (TC or PCR) in the GDH-toxin EIA algorithm, whereas only 2.3% of the total samples in GDH-PCR algorithm was discrepant and required another confirmatory test like TC.


Development of postgraduate training in critical care medicine for nurse practitioners and physician assistants.
Nurse practitioners (NPs) and physician assistants (PA) are increasingly providing care to the critically ill patients in the intensive care unit. We structured a 4-month training program for our existing NPs and PAs and assessed their knowledge and skill pre and post training. The program was composed of blended didactic in critical care medicine topics, critical care simulations in simulation laboratory, and supervised critical care procedures. Formal knowledge and skill assessments were performed before and after the program to assess success in meeting predefined learning objectives. The mean preintervention medical knowledge assessment score was 3.37 ± 0.56 SD, which significantly improved to 3.86 ± 0.46 SD (p < .00001). For clinical skills for critical care procedures, the mean preintervention score was 3.10 ± 0.86 SD, which improved to 3.61 ± 0.92 SD (p < .00001). The overall knowledge (including medical knowledge and clinical skills) improved from mean 3.30 ± 0.86 SD to 3.80 ± 0.42 SD. The improvement was seen regardless of the duration of experience in critical care medicine. We concluded that structured didactics with supervised procedural training along with dedicated training in simulation laboratories, even for a short period, improves the overall knowledge and clinical skills required to work in a critical care setting.


Global Prevalence of Diabetic Retinopathy in Pediatric Type 2 Diabetes: A Systematic Review and Meta-analysis.
Type 2 diabetes (T2D) is increasing globally. Diabetic retinopathy (DR) is a leading cause of blindness in adults with T2D; however, the global burden of DR in pediatric T2D is unknown. This knowledge can inform retinopathy screening and treatments to preserve vision in this population. To estimate the global prevalence of DR in pediatric T2D. MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the Cochrane Library, the Web of Science, and the gray literature (ie, literature containing information that is not available through traditional publishing and distribution channels) were searched for relevant records from the date of database inception to April 4, 2021, with updated searches conducted on May 17, 2022. Searches were limited to human studies. No language restrictions were applied. Search terms included diabetic retinopathy; diabetes mellitus, type 2; prevalence studies; and child, adolescent, teenage, youth, and pediatric. Three teams, each with 2 reviewers, independently screened for observational studies with 10 or more participants that reported the prevalence of DR. Among 1989 screened articles, 27 studies met the inclusion criteria for the pooled analysis. This systematic review and meta-analysis followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines for systematic reviews and meta-analyses. Two independent reviewers performed the risk of bias and level of evidence analyses. The results were pooled using a random-effects model, and heterogeneity was reported using χ2 and I2 statistics. The main outcome was the estimated pooled global prevalence of DR in pediatric T2D. Other outcomes included DR severity and current DR assessment methods. The association of diabetes duration, sex, race, age, and obesity with DR prevalence was also assessed. Among the 27 studies included in the pooled analysis (5924 unique patients; age range at T2D diagnosis, 6.5-21.0 years), the global prevalence of DR in pediatric T2D was 6.99% (95% CI, 3.75%-11.00%; I2 = 95%; 615 patients). Fundoscopy was less sensitive than 7-field stereoscopic fundus photography in detecting retinopathy (0.47% [95% CI, 0%-3.30%; I2 = 0%] vs 13.55% [95% CI, 5.43%-24.29%; I2 = 92%]). The prevalence of DR increased over time and was 1.11% (95% CI, 0.04%-3.06%; I2 = 5%) at less than 2.5 years after T2D diagnosis, 9.04% (95% CI, 2.24%-19.55%; I2 = 88%) at 2.5 to 5.0 years after T2D diagnosis, and 28.14% (95% CI, 12.84%-46.45%; I2 = 96%) at more than 5 years after T2D diagnosis. The prevalence of DR increased with age, and no differences were noted based on sex, race, or obesity. Heterogeneity was high among studies. In this study, DR prevalence in pediatric T2D increased significantly at more than 5 years after diagnosis. These findings suggest that retinal microvasculature is an early target of T2D in children and adolescents, and annual screening with fundus photography beginning at diagnosis offers the best assessment method for early detection of DR in pediatric patients.


The structure and light-dependent transient expression of a nuclear-encoded chloroplast protein gene from pea (Pisum sativum L.).
A nuclear gene encoding a light-induced transiently expressed protein that is localized in the chloroplast has been isolated from an EMBL3 library of pea DNA. The gene is a member of a multigene family. The sequence of the gene contains the complete reading frame of previously characterized cDNA clones and two introns in the 5' region of the protein coding sequence. Primer extension and S1 nuclease studies have defined the cap site. Two TATA boxes are found 5' to the initiating methionine codon. Only a limited homology is found between the presequence of the gene and transit sequences of other previously sequenced precursors. Isolated nuclei of pea have been labelled and the in vitro synthesized transcripts analysed. The results show that the light-dependent expression of the gene family is regulated at the level of transcription.


Two new species of stargazers of the genus Uranoscopus (Teleostei: Uranoscopidae) from the western Pacific Ocean.
Two new species of stargazers in the Uranoscopus albesca species-complex of the family Uranoscopidae are described from Papua New Guinea, which shares among other characters a concave posterodorsal margin of the pectoral fin. Uranoscopus brunneus n. sp. is described from a single specimen from off southwestern New Britain, and is characterised by lower edge of preopercle with 8 spines; labial fimbriae poorly-developed; anterior nostril with a long tubiform valve, posterior nostril a slit-like pore; supracleithrum with a sharp spine at rear end and five small spines inside; dorsoposterior margin of pectoral fin concave; 62 oblique scale-rows along the sides of the body in adult; pectoral-fin membranes dark brown. Uranoscopus kishimotoi n. sp., described from a single specimen from West Sepik Province, is characterised by the lower edge of preopercle with 3 spines; no labial fimbriae; both anterior and posterior nostrils with long tubiform valves; supracleithrum with a sharp spine at rear end and one additional small spine inside; dorso-posterior margin of pectoral fin concave; 59 oblique scale-rows along the sides of the body in adult; upper pectoral-fin membranes pale, lower membranes brown. The distribution of the species in the U. albesca species-complex is discussed.


Sex Differences in the Visuomotor Control of Obstacle Crossing When Walking Are Not Age Related.
To ensure stable obstacle crossing when walking, visual information is required two steps before reaching the obstacle. As possible age-related sex differences in visuomotor control have not been investigated, we assessed sex differences in obstacle crossing while walking, as examined by toe clearance (TC) and postural stability. Participants were 14 younger and 14 older adults (equal numbers of men and women) who wore goggles for visual field adjustment while obstacle crossing during gait. We manipulated three visual field occlusion conditions (total, lower, and no visual field occlusions) two steps before the obstacle and analyzed the TC of the lead limb, and the participants' step width and root mean square of trunk acceleration as indices of postural stability. We found a significant interaction between sex and visual condition in step width, with men showing larger step width values than women in all visual field conditions. Moreover, while women showed no step-width differences across visual field conditions, men had a larger step width with the lower visual field occluded than in the other visual conditions. We found no other significant sex differences. Our results suggest that men may be more dependent than women on the upper visual field for postural stability during obstacle crossing. Sex differences in visuomotor control were not affected by age.


Molecular anatomy and molecular design of channel proteins.
A central goal in membrane biology is to understand how channel proteins work in terms of their underlying protein structures. Ionic channels are symmetric (or pseudosymmetric) transmembrane protein assemblies organized around a central aqueous pore. The two key functional elements are the ionic channel, the actual polar pathway that permits the selective passage of 10(8) ions per second across the apolar core of the membrane lipid bilayer, and the sensor, the structure that detects the stimulus and couples it to the opening or closing (gating) of the channel. The current excitement in membrane protein science emerges from structural information that is providing clues about the molecular determinants of function: molecular cloning and sequencing has led to the elucidation of the primary structures of several superfamilies of voltage-gated and ligand-gated channels; channel proteins have been purified and reconstituted in lipid bilayers with full retention of function; the properties of many channel proteins have been characterized at the single-channel level; cDNA or RNA transcripts have been expressed in oocytes as functional proteins; specific peptide sequences predicted by molecular modeling to form the channel lining have been synthesized by solid-phase methods and proved to be channel formers in lipid bilayers. These advances are beginning to delineate general principles about the molecular design of this class of proteins that are essential for cellular excitability and signal transduction.


Water load test before and after PPI therapy in patients with gastro-oesophageal reflux disease.
Patients with gastro-oesophageal reflux disease may complain of epigastric pain, bloating, early satiety, epigastric fullness, epigastric burning, nausea and vomiting. To evaluate the symptoms in response to gastric distension and its relationship to a therapeutic course in patients with gastro-oesophageal reflux disease using the water load test, compared to healthy controls. Thirty gastro-oesophageal reflux disease patients with grade A oesophagitis (studied before and after 4 weeks of therapy with esomeprazole, 40 mg per day) and 15 patients with reflux-related symptoms demonstrated at wireless pH monitoring (non-erosive reflux disease) were compared to 30 healthy volunteers. Patients with grade A oesophagitis and with reflux-related symptoms ingested significantly lower water volumes than did controls, before onset of fullness, without statistically significant difference between erosive or non-erosive gastro-oesophageal reflux disease; this variable improved in patients after treatment. Nausea scores were higher basally in patients, pre- and post-therapy, and improved after therapy. Thirty-minute fullness and bloating scores improved after therapy in all gastro-oesophageal reflux disease patients compared to controls and pre-therapy. In all pre-treatment patients, a significant correlation was found only with epigastric fullness; after treatment, there was no significant relationship between the water load and the symptom scores. In patients with reflux-related symptoms, with or without grade A oesophagitis, the water load test is frequently abnormal, suggesting an altered gastric function. This could explain the incomplete resolution of symptoms after treatment in some patients, and should lead to additional studies aimed at exploring gastric function in gastro-oesophageal reflux disease patients.


On comparing in vivo intracranial recordings in non-human primates to predictions of optimized transcranial electrical stimulation.
Transcranial electrical stimulation (tES) can be optimized to achieve maximal current flow at desired brain regions. The aim of this study was to characterize electric field magnitudes generated by tES optimization and to compare them to experimentally induced values as determined by data from intracranial electrodes. Local field potentials were recorded from two monkeys with implanted multi-site intracranial Utah arrays during transcranial direct current stimulation (tDCS), and the neural effect predictions obtained from optimized electrode placement were assessed. Comparative data between the two sites of intracranial recordings during tDCS partially validated the predictions of our tES optimization algorithms.


DNA Damage and Repair in Vascular Disease.
DNA damage affecting both genomic and mitochondrial DNA is present in a variety of both inherited and acquired vascular diseases. Multiple cell types show persistent DNA damage and a range of lesions. In turn, DNA damage activates a variety of DNA repair mechanisms, many of which are activated in vascular disease. Such DNA repair mechanisms either stall the cell cycle to allow repair to occur or trigger apoptosis or cell senescence to prevent propagation of damaged DNA. Recent evidence has indicated that DNA damage occurs early, is progressive, and is sufficient to impair function of cells composing the vascular wall. The consequences of persistent genomic and mitochondrial DNA damage, including inflammation, cell senescence, and apoptosis, are present in vascular disease. DNA damage can thus directly cause vascular disease, opening up new possibilities for both prevention and treatment. We review the evidence for and the causes, types, and consequences of DNA damage in vascular disease.


Aarhus Regenerative Orthopaedics Symposium (AROS).
The combination of modern interventional and preventive medicine has led to an epidemic of ageing. While this phenomenon is a positive consequence of an improved lifestyle and achievements in a society, the longer life expectancy is often accompanied by decline in quality of life due to musculoskeletal pain and disability. The Aarhus Regenerative Orthopaedics Symposium (AROS) 2015 was motivated by the need to address regenerative challenges in an ageing population by engaging clinicians, basic scientists, and engineers. In this position paper, we review our contemporary understanding of societal, patient-related, and basic science-related challenges in order to provide a reasoned roadmap for the future to deal with this compelling and urgent healthcare problem.


New tension band material for fixation of transverse olecranon fractures: a biomechanical study.
This study tested the use of braided polyethylene cable as an option for repairing transverse olecranon fractures. Six cadaveric elbows underwent a transverse olecranon osteotomy followed by fixation with tension band constructs using 18-gauge wire and Secure-Strand (U.S. Surgical, North Haven, Conn). Distraction forces up to 450 N were applied to the triceps tendon while measuring fracture displacement with an extensometer. The average maximal fracture gap with the standard AO tension band technique using stainless steel wire was 0.66 +/- 0.43 mm, as opposed to 0.68 +/- 0.45 mm with braided polyethylene cable. A paired t test indicated no significant difference between the two materials. These results support the feasibility of braided polyethylene cable as an alternative to the standard steel-wire tension band.


Stimulation of epithelial cell proliferation of isolated distal colon of rats by continuous colonic infusion of ammonia or short-chain fatty acids is nonadditive.
Dietary fibers accelerate colonic epithelial cell proliferation at least in part by modulating bacterial metabolism in the large intestine. Ammonia and short-chain fatty acids (SCFA) are major metabolites of hindgut bacteria and are believed to affect epithelial cell kinetics of the colon. However, the effect of luminal ammonia itself and the possible interaction of ammonia with SCFA on colonic epithelial cell proliferation have not yet been studied. The colon of rats was surgically isolated and continuously administered infusates with saline, ammonia, SCFA or both into the isolated colon for 7 d in a two-way factorial design. On d 7, vincrystine sulfate was administered intravenously to cause metaphase arrest. The activity of epithelial cell proliferation in the distal colon was estimated by using a stathmokinetic method and by histologic examination. The crypt size was significantly larger in rats given infusates containing SCFA than in rats given infusates without SCFA. Infusion of ammonia or SCFA significantly stimulated colonic epithelial cell proliferation compared with the saline infusion. Infusion of both ammonia and SCFA resulted in accumulated mitoses per crypt that did not differ from the other three infusions although the value tended to be lower than when SCFA alone were infused. Thus, stimulation of epithelial cell proliferation by ammonia and SCFA is not additive, and the interaction between them should be considered when the effects of dietary fibers on gut epithelial proliferation are investigated.


Expression of inflammatory cytokines in ovarian epithelial cancer and their correlation.
This study investigates the expression of interleukin (IL)-17 (IL-17A and IL-17D) and its role in ovarian epithelial tumor and its correlation with the clinical characteristics. Fifty malignant ovarian epithelial tumor specimens were collected after surgery and set as group A. Ten benign epithelioma specimens and ten normal epithelial specimens were set as group B and C, respectively. The expression of IL-17A and IL-17D in the three groups was detected using the EnVision method, and the correlation of positive expression rate with pathological type, clinical stage, presence of ascites and differentiation degree was analyzed. Group A had higher expression of IL-17A and IL-17D compared to group B and C (p less than 0.05). The expression rate was in correlation to clinical stage and differentiation degree, but in no correlation to pathological type and presence of ascites. The expression rate of malignant epithelioma in the early stage was lower than that in the late stage (p less than 0.05). Lower differentiation degree indicated higher expression rate (p less than 0.05). Pathological type and presence of ascites had no remarkable influence on the expression rate (p>0.05). Study of the expression of IL-17 provides theoretical support for the clinical treatment and prognosis prediction of ovarian epithelial tumor.


Osteoclast formation during tumor osteolysis does not require proliferating osteoclast precursor cells.
The cellular mechanism or mechanisms through which tumors induce osteoclast formation at sites of tumor osteolysis is unknown. To test the hypothesis that osteoclast formation at sites of tumor osteolysis reflects influences that tumors have on proliferating osteoclast precursor cells, a novel in vivo experimental model was developed that produced mice that were deficient in osteoclasts (op/op) and were depleted (by way of total body irradiation) of proliferating osteoclast precursor cells. The femora of irradiated op/op mice were injected with tumor cells (2472 clone) that had been previously shown to form osteolytic tumors and to induce focal osteoclastogenesis, and the influence of these tumor cells on osteoclast formation was determined in op/op mice that were depleted of proliferating osteoclast precursor cells. The results indicated that 2472 tumor cells induced osteoclast formation in op/op mice despite the absence of proliferating osteoclast precursor cells. This finding disproved the hypothesis under investigation and suggests that osteoclast formation at sites of tumor osteolysis reflects influences of tumors on postmitotic, not proliferating, osteoclast precursor cells.


Modifying internal organization and surface morphology of siRNA lipoplexes by sodium alginate addition for efficient siRNA delivery.
Vectorized small interfering RNAs (siRNAs) are widely used to induce specific mRNA degradation in the intracellular compartment of eukaryotic cells. Recently, we developed efficient cationic lipid-based siRNA vectors (siRNA lipoplexes or siLex) containing sodium alginate (Nalg-siLex) with superior efficiency and stability properties than siLex. In this study, we assessed the physicochemical and some biological properties of Nalg-siLex compared to siLex. While no significant differences in size, ζ potential and siRNA compaction were detected, the addition of sodium alginate modified the particle morphology, producing smoother and heterogeneous particles characterized by transmission electron microscopy. We also noted that Nalg-siLex have surface differences observed by X-ray photoelectron spectroscopy. These differences could arise from an internal reorganization of components induced by the addition of sodium alginate, that is indicated by Small-Angle X-ray Scattering results. Moreover, Nalg-siLex did not trigger significant hepatotoxicity nor inflammatory cytokine secretion compared to siLex. Taken together these results suggest that sodium alginate played a key role by structuring and reinforcing siRNA lipoplexes, leading to more stable and efficient delivery vector.


MR imaging-based evaluation of morphological changes in the uterus and ovaries of patients following neoadjuvant chemotherapy for cervical cancer.
We used magnetic resonance (MR) imaging and hormonal levels to evaluate the influence of chemotherapy for cervical cancer on female pelvic reproductive organs. We retrospectively evaluated 16 pre- and 11 postmenopausal patients with cervical cancer who underwent neoadjuvant chemotherapy (NACT) and radical surgery. We evaluated morphological changes in the uterus and ovaries by MR imaging both quantitatively and qualitatively, measuring the volume of the uterine body and bilateral ovaries, endometrial thickness, and signal intensity of the myometrium and bilateral ovaries and assessing visibility of the junctional zone and bilateral ovarian follicles. We compared both quantitative and qualitative factors between pre- and post-NACT. Pre- and post-NACT hormonal values of estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) of 8 patients in the premenopausal group were obtained and analyzed statistically. In the premenopausal group, we observed a statistically significant decrease in all quantitative parameters as well as in the visibility of the left ovarian follicle. In the postmenopausal group, only endometrial thickness changed significantly. Premenopausal patients showed a statistically significant decrease in levels of progesterone, FSH, and LH after chemotherapy. MR demonstrated changes in the uterus and ovaries in premenopausal subjects who underwent chemotherapy that resembled those changes classically reported in physiological postmenopausal subjects. These changes are likely due to ovarian toxicity and secondary hormonal changes. MR imaging might be a valuable tool for obtaining information regarding chemotherapy-induced infertility.


Medical abortion in the second trimester.
The introduction of prostaglandin analogues and mifepristone has changed the management of second trimester abortion in the last 2 decades. Gemeprost and misoprostol are the two most extensively studied prostaglandin analogues that are used in this period. The combination of either gemeprost or misoprostol with mifepristone is most effective. With these regimens, over 90% of women abort within 24 hours and the mean induction to abortion interval is about 6 hours. Mifepristone is expensive and is not available in many countries. Therefore, prostaglandin analogue-only regimens might be the only option. These regimens are still effective with an abortion rate of >90% in 48 hours. However, the induction to abortion interval (15 hours) is much longer. Intra-cervical tents can be used to shorten the induction to abortion intervals.


A conserved sequence element is present around the transcription initiation site for RNA polymerase A in Saccharomycetoideae.
To identify DNA elements involved in the initiation of rRNA transcription in yeast we located the start site of the rRNA operon of Kluyveromyces lactis and Hansenula wingei, both members of the Saccharomycetoideae, by S1 nuclease analysis and determined the surrounding nucleotide sequences. Comparison of these sequences with those of Saccharomyces carlsbergensis, S. cerevisiae and S. rosei (all belonging to the same yeast subfamily) reveals an identical sequence at the site of transcription initiation from position +1 to +7 which is part of a larger conserved region extending from position -9 to +23; the conserved heptanucleotide sequence is supposed to constitute an important part of the promoter for yeast RNA polymerase A. The non-transcribed spacers (NTS) upstream of position -9 have diverged strongly with the exception of two short elements around positions -75 and -135. The external transcribed spacer (ETS) downstream of position +23 is largely conserved between K. lactis, S. rosei and S. carlsbergensis except for a divergent region around position +75. On the other hand, the ETS of H. wingei has diverged significantly.


The use of intra-abdominal prophylactic drainage in laparoscopic cholecystectomy: does it change in relation to surgical expertise? A multicenter case-control retrospective study on postoperative outcomes.
The routine use of abdominal drainage (AD) after laparoscopic cholecystectomy (LC) is still controversial. The aim of this expertise-based study is to evaluate the efficacy of prophylactic AD in terms of postoperative complications and analyze the factors linked to AD placement. This case-control retrospective study included patients with cholelithiasis who underwent LC with AD (AD group) and LC without drainage (no-AD group) in two Italian centers. Allocation to groups was non-randomized and based on surgeons' decisions. Patient's characteristics, operative results, postoperative outcomes, surgeon's expertise related data were compared between the two groups with univariate and multivariate analysis. Patients in the two groups were comparable for age, sex ratio, and morbidity. Length of postoperative hospital stay (LOS) in the no-AD group was shorter than the AD group. Patients in the AD group had a higher rate of wound infection. No difference in postoperative pain measured 7 days after the surgery was found. Our results show an association between the first operator's expertise and age and the decision of placing the AD. The operative time seems to be the principal factor impacting the decision whether to place or not the AD. Our results indicate that it is feasible not to insert routine AD after elective LC for cholelithiasis. The use of AD seems to cause more cases of postoperative wound infections, prolongs the LOS and the operative time. The drain placement choice seems to change in relation to the surgeon's expertise.


Nutritional Sustainability Inside-Marketing Sustainability as an Inherent Ingredient.
Current discussions about the concept of nutritional sustainability show a high complexity of this topic leading to many different definitions. Regarding communication issues of nutritional sustainability between actors of food chains this complexity should be reduced. One opportunity to tackle these challenges of reducing complexity might be the concept of ingredient branding. Therefore, the aim of this mini-review is the identification of conditions for ingredient branding application as a communication strategy for nutritional sustainability which might overcome challenges in communicating the complexity between the different stakeholders of supply chains. In doing so, the specific case of agrifood chains is discussed based on the selected characteristics of globalization, increasing consumer demands, foods incorporating credence attributes and price. Along the agrifood chain, a sourcing strategy reflecting nutritional and sustainable aspects might lead to an ingredient branding strategy implying a brand policy for a special ingredient within the final product which is an important component but cannot be clearly recognized by the user. A "nutritional sustainability inside" strategy should reflect the multifaceted information along the agrifood chain and should be based on standardized criteria for nutritional sustainability.


Hhex Regulates Hematopoietic Stem Cell Self-Renewal and Stress Hematopoiesis via Repression of Cdkn2a.
The hematopoietically expressed homeobox transcription factor (Hhex) is important for the maturation of definitive hematopoietic progenitors and B-cells during development. We have recently shown that in adult hematopoiesis, Hhex is dispensable for maintenance of hematopoietic stem cells (HSCs) and myeloid lineages but essential for the commitment of common lymphoid progenitors (CLPs) to lymphoid lineages. Here, we show that during serial bone marrow transplantation, Hhex-deleted HSCs are progressively lost, revealing an intrinsic defect in HSC self-renewal. Moreover, Hhex-deleted mice show markedly impaired hematopoietic recovery following myeloablation, due to a failure of progenitor expansion. In vitro, Hhex-null blast colonies were incapable of replating, implying a specific requirement for Hhex in immature progenitors. Transcriptome analysis of Hhex-null Lin- Sca+ Kit+ cells showed that Hhex deletion leads to derepression of polycomb repressive complex 2 (PRC2) and PRC1 target genes, including the Cdkn2a locus encoding the tumor suppressors p16Ink 4a and p19Arf . Indeed, loss of Cdkn2a restored the capacity of Hhex-null blast colonies to generate myeloid progenitors in vitro, as well as hematopoietic reconstitution following myeloablation in vivo. Thus, HSCs require Hhex to promote PRC2-mediated Cdkn2a repression to enable continued self-renewal and response to hematopoietic stress. Stem Cells 2017;35:1948-1957.


'On Water'-Promoted Three-Component Tandem Michael Addition/D-A Cycloaddition Reaction to Construct Polycyclic N-Heterocycles Derivatives.
'On Water'-promoted the three-component tandem Michael addition/D-A cycloaddition reaction in 80 °C at 3 h has been developed without employing any catalyst and organic solvent. The process allows facile access to polycyclic N-heterocycles derivatives contain indole and maleimide from easily accessible starting materials in moderate to high yields (up to 91 %). Compared with conventional reaction conditions, this reaction not only improves the reaction efficiency and rate but also minimizes the side reaction.


Acute and chronic effects of resistance exercise on blood pressure in elderly women and the possible influence of ACE I/D polymorphism.
This study investigated the chronic effect of blood pressure (BP) and post-exercise hypotension (PEH) during resistance training (RT) and its relation with the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism in hypertensive elderly women. Participants were divided into two groups: an experimental group (EG) with exercise and a control group (CG) without exercise. The EG performed one adaptation month and one repetition maximum load (1RM) test at the end of this period. After the first month, the EG conducted a three-month program of RT at 60%, 70%, and 80% of 1RM, respectively, for each month. The CG was evaluated at the end of each month. Systolic (SBP) and diastolic (DBP) blood pressure (Microlife BP 3AC1-1) were measured, with the subject in a seated position, during an acute session for both GE and CG as follows: every 5 minutes for 20 minutes at pre-exercise rest, immediately after the resistance exercise and control, and every 15 minutes during 1 hour of recovery after exercise and CG. Analysis of covariance showed reduction in SBP and DBP (P ≤ 0.05) rest values after the RT program. PEH was observed only for the EG in acute sessions, for SBP after the second and third months (P ≤ 0.05), and for DBP after the second and fourth months (P ≤ 0.05). No significant differences in main effects and interaction effects between blood pressure and ACE I/D were observed. The occurrence of chronic reduction of blood pressure and PEH through EG may have a protective effect on the cardiovascular system with no ACE I/D polymorphism influence for this population.


Localisation and activity of cathepsins K and B in equine osteoclasts.
Cathepsin K and cathepsin B were immunolocalised in equine osteoclasts (OC s) present in ex vivo cartilage/subchondral bone samples. Samples were obtained post mortem from the lateral trochlear ridge (LTR) of six horses and ponies aged between 303 days gestation to 8 months. Strong expression of cathepsin K was detected in OC s, particularly those located at the osteochondral junction, apparently involved in the resorption of calcified cartilage. Cathepsin K expression was also detected in hypertrophic chondrocytes and in the endothelial cells of some blood vessels penetrating the hypertrophic zone of cartilage. By contrast, cathepsin B was either absent or present at very low levels in OC s.Osteoclast-like cells (OCL s) were generated in vitro from bone marrow (BM), obtained from the femurs of one horse and two ponies. High levels of cathepsin K activity but only very low levels of cathepsin B activity were demonstrated in OCL s using fluorogenic substrates for these enzymes. The cathepsin K activity could be blocked by the general cysteine proteinase inhibitor, E-64, but not by the cathepsin B inhibitor, CA-074Me. The cathepsin B activity was completely blocked by both CA-074Me and E-64. Taken together, these results suggest that cathepsin K is more important than cathepsin B in the osteoclastic resorption of bone and calcified cartilage of developing equine long bones. Given the apparent importance of cathepsin K in equine endochondral ossification further investigation into the possibility that abnormal expression of this enzyme is involved in the pathogenesis of equine developmental orthopaedic disease is warranted.


[Septic focus in the retroperitoneum--iatrogenic foreign body of cotton (gossypiboma)].
Retained surgical towels (gossypiboma) present a diagnsotic problem if they remain asymptomatic for many years. We report on one 51 year old patient with repeated septic temperatures in the early post-operative phase after hemicolectomy. The contrast enhanced CT of the abdomen revealed a well-defined round soft-tissue mass with a dense, enhanced wall containing an internal high-density wavy and striped area. At laparotomy a secondary infected surgical sponge with abscess formation was found.


Clinicomycological Study of Dermatophytosis in South India.
Dermatophytic infections are commonly encountered a problem and constitute more than 50% of cases in dermatology outpatient departments. Diagnosis of these infections requires the proper use of laboratory methods. This study was conducted to know the etiology of dermatophytosis in patients attending Tertiary Care Level Hospital in South India and to compare the efficacy of Sabouraud's dextrose agar (SDA) with actidione and dermatophyte test medium (DTM) in isolating and identifying dermatophytes. A total of 110 samples which included 101 skin samples and 9 hair samples from clinically suspected dermatophytosis were collected. Direct microscopy by KOH and culture on SDA with actidione and DTM were done. Of 110 samples collected, 58.18% were KOH positive for fungal filaments and 56.36% were culture positive for dermatophytes. More number of cases were observed between age groups of 21-40 years. Males were more affected compared to females. Tinea corporis was the common clinical presentation observed (40%). Trichophyton rubrum (58.06%) was the predominant isolate recovered in all clinical presentations but Trichophyton violaceum was the most common isolate in tinea capitis. All culture positives were grown on both SDA with actidione and DTM. Appearance of growth was earlier on DTM that is, within 10 days compared to SDA with actidione where growth started appearing only after 10 days. This is statistically significant P < 0.0001 (χ(2) = 71.6). Species level identification on primary isolation was possible when grown on SDA with actidione and it was not possible with the growth on DTM on primary isolation. DTM is a good screening medium in laboratory diagnosis of dermatophytosis when compared to SDA with actidione. But DTM is inferior to SDA with actidione in identification of dermatophyte species.


Nitrogen fixation by corona discharge on the early precambrian Earth.
We report the first experimental study of nitrogen fixation by corona discharge on the anoxic primitive Earth. The energy yields of nitric oxide (NO) and nitrous oxide (N(2)O) were experimentally determined over a wide range of CO(2)-N(2) mixtures simulating the evolution of the Earth's atmosphere during the Hadean and Archean eras (from 4.5 ba to 2.5 ba). NO, the principal form of fixed nitrogen in lightning and coronal discharge in early Earth, is produced ten times less efficiently in the latter type of electrical discharge with an estimated maximum annual production rate of the order of 10(10) g yr(-1). For N(2)O the maximum production rate was estimated to be approximately 10(9) g yr(-1). These low rates of syntheses indicate that corona discharges as point discharges on the clouds and ground did not play a significant role in the overall pool of reactive nitrogen needed for the emergence and sustainability of life.


To the bitter end: disparities in end-of-life care.
Although technological advancements have provided the means to sustain life and provide care regardless of whether the treatment is appropriate and compassionate given the condition of the patient, bioethical, legal, and moral concerns related to disparities in care still arise in the United States. These concerns call into question the necessity to continue life-sustaining or palliative care treatments when patients and/or families are faced with end-of-life decisions. This study will focus on various historical, clinical cultural, and ethical issues that have placed this dilemma into a controversial public spectrum, by using case studies retrieved from referenced literature, which illustrate disparities in care at the end of life.


Improved Breast 2D SWE Algorithm to Eliminate False-Negative Cases.
Two-dimensional shear wave elastography (SWE) has been limited in breast lesion characterization due to false-negative results from artifacts. The aim of this study was to evaluate an updated Food and Drug Administration-approved breast 2D-SWE algorithm and compare with the standard algorithm (SA). This prospective, single-center study was approved by our local institutional review board and Health Insurance Portability and Accountability Act compliant. From April 25, 2019 to May 2, 2022, raw shear wave data were saved on patients having screening or diagnostic breast ultrasound on a Siemens Sequoia US. After removing duplicate images and those without biopsy diagnosis or stability over 2 years, there were 298 patients with 394 lesions with biopsy-proven pathology or >2-year follow-up. Raw data were processed using the SA and a new algorithm (NA). Five-millimeter regions of interest were placed in the highest stiffness in the lesion or adjacent 3 mm on the SA. Stiffness values (shear wave speed, max) in this location from both algorithms were recorded. Statistics were calculated for comparing the 2 algorithms. The mean patient age was 56.3 ± 16.1 years (range, 21-93 years). The mean benign lesion size was 10.7 ± 8.0 mm (range, 2-46 mm), whereas the mean malignant lesion size was 14.9 ± 7.8 mm (range, 4-36 mm). There were 201 benign (>2-year follow-up) and 193 biopsied lesions (65 benign; 128 malignant). The mean maximum stiffness for benign lesions was 2.37 m/s (SD 1.26 m/s) for SA and 3.51 m/s (SD 2.05 m/s) for NA. For malignant lesions, the mean maximum stiffness was 4.73 m/s (SD, 1.71 m/s) for SA and 8.45 m/s (SD, 1.42 m/s) for NA. The area under the receiver operating characteristic curve was 0.87 SA and 0.95 NA when using the optimal cutoff value. Using a threshold value of 5.0 m/s for NA and comparing to SA, the sensitivity increased from 0.45 to 1.00 and the specificity decreased from 0.94 to 0.81; the positive predictive value was 0.72, the negative predictive value was 1.00, and the negative likelihood ratio was 0.00. Using a new breast SWE algorithm significantly improves the sensitivity of the technique with a small decrease in specificity, virtually eliminating the "soft" cancer artifact. The new 2D-SWE algorithm significantly increases the sensitivity and negative predictive value in characterizing breast lesions as benign or malignant and allows for downgrading all BI-RADS 4 lesions.


A warning about measurement and methodological issues associated with coronavirus tracking and evaluation across jurisdictions.
As people around the world experience a devastating pandemic, it is critical that policy-makers consider the methodological and measurement issues that might be associated with coronavirus disease 2019 (COVID-19) public health indicators. This commentary uses four primary variables to illustrate measurement and methodological issues that can complicate comparisons between jurisdictions. Jurisdiction refers to a variety of geographic areas, such as a country, a state, or a province/territory. These variables play a critical role in determining how we understand the trajectory of disease spread. These variables also contribute to our understanding of prevention strategies and their associated efficacy, reflecting the impact of COVID-19 on hospitals. It is critical for public health stakeholders and the public to recognize that these four simple variables can vary substantially across jurisdictions.


Self-esteem, spiritual well-being, and intimacy: a comparison among couples using NFP and oral contraceptives.
The purpose of this study was to compare the intimacy, spiritual well being (SWB), and self-esteem of couples using natural family planning (NFP) with those couples using oral contraceptives (OCs). 22 couples who were using the Creighton Model Ovulation Method of NFP for 1 year to avoid pregnancy were matched with 22 couples who were using OCs for a least a 1-year period and administered a SWB, self-esteem, and intimacy inventory. Student t-tests were calculated to determine differences in the mean scores of the 3 inventories between the 2 groups. The results showed that the NFP couples had statistically higher self-esteem (T=3.15, p0.01), SWB (T=4.25. p0.001), and intellectual intimacy (T=2.53, p0.05) than the OC couples. There were no differences in emotional, social, recreational, and sexual intimacy between the groups. Although the results provide some evidence that NFP can enhance a couple's relationship, other factors such as a sampling bias and educational levels could explain the difference.


Hypovitaminosis D is associated with reductions in serum apolipoprotein A-I but not with fasting lipids in British Bangladeshis.
Although hypovitaminosis D has been suggested to increase the risk of heart disease, its relation to components of the fasting lipid profile has not been clarified for specific ethnic groups. The objective was to determine the relation of circulating 25-hydroxyvitamin D [25(OH)D] concentrations to fasting lipid concentrations in South Asian subjects at risk of hypovitaminosis D. The present study was conducted in 170 British Bangladeshi adults, 69 men and 101 women, from east London who were free of known diabetes or chronic disorders. Vitamin D repletion was assessed by measuring fasting serum 25(OH)D concentrations. Fasting lipid profiles were measured as part of a study of the risk factors for type 2 diabetes and ischemic heart disease, which included hypovitaminosis D. A univariate analysis showed that total cholesterol, LDL cholesterol, and both apolipoprotein (apo) A-I and apo B concentrations correlated directly with serum 25(OH)D concentrations. However, a multiple regression analysis, which included all the documented risk factors for diabetes and ischemic heart disease, showed that the 25(OH)D concentration (vitamin D status) was an independent predictor of increasing apo A-I concentrations (standardized coefficient beta = 0.3; P < 0.001) but not of fasting lipid concentrations. In this study of British South Asians, the data showed a positive relation of fasting apo A-I concentrations to serum 25(OH)D concentrations, independent of glycemia and other dietary, anthropometric, and lifestyle risk factors for type 2 diabetes and ischemic heart disease after multiple regression analyses. Subjects with hypovitaminosis D are likely to have an increased risk of ischemic heart disease independent of their increased risk of type 2 diabetes.


Interactions between the archaeal Cdc6 and MCM proteins modulate their biochemical properties.
The origin recognition complex, Cdc6 and the minichromosome maintenance (MCM) complex play essential roles in the initiation of eukaryotic DNA replication. Homologs of these proteins may play similar roles in archaeal replication initiation. While the interactions among the eukaryotic initiation proteins are well documented, the protein-protein interactions between the archaeal proteins have not yet been determined. Here, an extensive structural and functional analysis of the interactions between the Methanothermobacter thermautotrophicus MCM and the two Cdc6 proteins (Cdc6-1 and -2) identified in the organism is described. The main contact between Cdc6 and MCM occurs via the N-terminal portion of the MCM protein. It was found that Cdc6-MCM interaction, but not Cdc6-DNA binding, plays the predominant role in regulating MCM helicase activity. In addition, the data showed that the interactions with MCM modulate the autophosphorylation of Cdc6-1 and -2. The results also suggest that MCM and DNA may compete for Cdc6-1 protein binding. The implications of these observations for the initiation of archaeal DNA replication are discussed.


Poor responders: does the protocol make a difference?
An inadequate response to gonadotropins during in-vitro fertilization treatment may result in cycle cancellation, fewer embryos available for transfer and decreased pregnancy rates. For these reasons, numerous strategies to improve ovarian stimulation in poor responders have been proposed. These include variations in the type, dose and timing of gonadotropins, gonadotropin-releasing hormone agonists and gonadotropin-releasing hormone antagonists. Unfortunately, despite optimism generated by studies using retrospective controls, epidemiologically sound trials have been scarce. Indeed, of the three prospective randomized trials performed in poor responders to date no compelling advantage for one stimulation protocol over another has been established. Although this lack of improvement may reflect inadequate sample sizes, an alternative explanation is simply that the protocol, after a certain point, does not make a difference. Aside from oocyte donation, greater hope for poor responders may rest in aneuploidy screening, in-vitro oocyte maturation and cytoplasm/nuclear transfer.


Management of Metastatic Bone Disease Algorithms for Diagnostics and Treatment.
Bone is a frequent site of metastases in advanced cancer and is associated with significant skeletal morbidity. Current treatment options are aimed at preserving and improving functional independence and quality of life. A review of current literature focusing on diagnostic tools and treatment approaches of bone metastasis in advanced cancer was performed and conclusions were incorporated into diagnostic and treatment algorithms. Radiologic imaging has added valuable tools for screening and diagnostics of bone metastasis. Clinical management of skeletal metastasis includes improved pain management, introduction of bone modifying agents and advancements in surgical and radiation therapy. We propose three algorithms enhancing the sensitivity of diagnostics and improving multidisciplinary management of vertebral and non-vertebral bone metastasis. Bone metastases are an expression of a systemic disease. Treatment options include highly specialized modalities yet need to be tailored to individual needs. Algorithms help standardize treatment procedures and can improve treatment outcome in a multidisciplinary setting.


Outcomes in the Era of Interferon-Free Direct-Acting Antiviral Therapy After Liver Transplantation in Patients with Hepatitis C Virus and Hepatocellular Carcinoma.
Several studies have shown improved outcome of liver transplant (LT) recipients with hepatitis C virus (HCV) since the widespread clinical use of interferon-free direct-acting antivirals (IFN-free DAAs). However, the association of IFN-free DAA therapy on tumor characteristics and on the outcome of LT in patients with hepatocellular carcinoma (HCC) has not been studied. We aimed to examine pre-transplant HCC characteristics and post-LT outcomes in the IFN-based DAA treatment and IFN-free DAA treatment eras. Using the United Network for Organ Sharing/Organ Procurement and Transplantation Network database, we analyzed adults with a diagnosis of HCV and HCC who received LTs from deceased donors from 04/2012 to 12/2017. Cox regression models were used to identify the association between the IFN-based DAA treatment vs IFN-free DAA treatment era and study outcomes (mortality, graft failure, and HCC recurrence at 1 and 3 years). Complete tumor necrosis was significantly higher in the IFN-free DAA treatment era (22.73% vs 18.22%; P <0.01). No other HCC tumor characteristics differed significantly between the two eras. HCC recurrence rates were similar between the two eras. On multivariate Cox regression analysis, patients who had transplants in the IFN-free DAA treatment era had lower risk of graft failure compared with the IFN-based DAA treatment group (hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.25-0.77; P <0.01). Patient mortality was lower in the IFN-free DAA treatment era although the difference was not statistically significant (HR, 0.82; 95% CI, 0.60-1.13; P =0.22). LT recipients in the IFN-free DAA treatment era had significantly higher complete tumor necrosis in explants. Other HCC tumor characteristics were similar between the two eras. Post-LT graft failure at 1 and 3 years significantly decreased in the IFN-free DAA treatment era among patients with HCV and HCC, although patient mortality was not statistically different.


Reference values for basic human anatomical and physiological characteristics for use in radiation protection.
A new publication prepared by the ICRP Task Group on Reference Man, Basic anatomical and physiological data for use in radiological protection: reference values, is focused on those human characteristics that are important for dosimetric calculations. Moving from the past emphasis on a Reference Man, the new report presents a series of reference values for both male and female subjects of six different ages--newborn, 1, 5, 10, 15 y, and adult. In selecting reference values, the task group has used data on Western Europeans and North Americans because these populations have been well studied with respect to anatomy, body composition and physiology. When appropriate, comparisons are made between the chosen reference values and data from several Asian populations. The reference values for height and body mass are higher than those reported for various Asian populations. However, the reported masses of individual organs and tissues, particularly for China and Japan, are similar to the reference values.


Asking the questions and offering solutions: the ongoing dialogue between the primary care physician and the patient with erectile dysfunction.
Primary care physicians are becoming more involved in inquiry about and management of erectile dysfunction (ED). This relatively new occurrence is appropriate considering that the presence of ED may signal potentially serious medical conditions and that ED is a condition with true morbidity. Addressing sexual issues in the office setting requires a comforting and secure atmosphere in which patients can easily discuss their problems. Because many men are hesitant to approach physicians with their sexual problems, clinicians need to be proactive by asking direct questions, either verbally or in a written history format. The clinician who learns of a patient's ED should acknowledge it as a legitimate problem and either work with the patient on a management plan or refer him to a physician more prepared to successfully manage the condition. Clinicians who choose to treat men with ED can achieve higher success rates by including the partner in the discussions and treatment planning and by offering some basic sex counseling. These efforts require additional learning on the part of the clinician, but the rewards of managing sexual dysfunction include happier and healthier patients and improved patient-partner relationships.


Tailor-made purified human platelet lysate concentrated in neurotrophins for treatment of Parkinson's disease.
Human platelet lysates (PLs), which contain multiple neurotrophins, have been proposed for treating neurodegenerative disorders, including Parkinson's disease (PD). However, current PLs suspended in plasma have high protein content and contain fibrinogen/fibrin and, following activation, also proteolytic and thrombogenic enzymes. Upon brain administration, such PLs may saturate the cerebrospinal fluid and exert neurotoxicity. We assessed whether purified PLs, concentrated in neurotrophins, protected dopaminergic neurons in PD models. Platelet concentrates were collected by apheresis and centrifuged to eliminate plasma and recover the platelets. Platelets were lysed by freeze-thaw cycles, and the 10-fold concentrated platelet pellet lysates (PPLs) were heat-treated (at 56 °C for 30 min). The heat-treated PPLs were low in total proteins, depleted in both plasma and platelet fibrinogen, and devoid of thrombogenic and proteolytic activities. They exerted very high neuroprotective activity when non-oncogenic, Lund human mesencephalic (LUHMES) cells that had differentiated into dopaminergic neurons were exposed to the MPP+ neurotoxin. Heat treatment improved the neuroprotection and inactivated the neurotoxic blood-borne hepatitis C virus. PPL did not induce inflammation in BV2 microglial cells and inhibited COX-2 expression upon lipopolysaccharide exposure. Intranasal administration in mice revealed (a) diffusion of neurotrophins in the striatum and cortex, and (b) MPTP intoxication neuroprotection in the substantia nigra and striatum and the absence of neuroinflammation. These dedicated heat-treated PPLs can be a safe and valuable candidate for a therapeutic strategy for PD.


Sequencing of oligoarabinosyl units released from mycobacterial arabinogalactan by endogenous arabinanase: identification of distinctive and novel structural motifs.
The mycobacterial D-arabinofuran is a common constituent of both cell wall mycolyl-arabinogalactan (AG) and the associated lipoarabinomannan (LAM), and is thus accorded critical structural and immunological roles. Despite a well-recognized importance, progress in understanding its full structural characteristics beyond the nonreducing terminal motifs has hitherto been limited by available analytical tools. An endogenous arabinanase activity recently isolated from Mycobacterium smegmatis was previously shown to be capable of releasing large oligoarabinosyl units from AG. Advanced tandem mass spectrometry utilizing both low and high energy collision induced dissociation now afforded a facile way to map and directly sequence the digestion products which were dominated by distinctive Ara18 and Ara19 structural units, together with Ara7 and lesser amount of Ara11 and Ara12. Significantly, evidence was obtained for the first time which validated the linkages and branching pattern of the previously inferred Ara22 structural motif of AG, on which the preferred cleavage sites of the novel arabinanase could be localized. The established linkage-specific MS/MS fragmentation characteristics further led to identification of a galactosamine substituent on the C2 position of a portion of the internal 3,5-branched Ara residue of the AG of Mycobacterium tuberculosis, but not that of the nonpathogenic, fast growing M. smegmatis.


Cost-effectiveness of diagnostic tests for toenail onychomycosis: a repeated-measure, single-blinded, cross-sectional evaluation of 7 diagnostic tests.
Our purpose was to estimate and compare the cost-effectiveness of the most commonly used diagnostic tests for onychomycosis: potassium hydroxide preparation (KOH), interpreted both by a dermatologist (KOH-CLINIC) and a laboratory technician (KOH-LAB); KOH with dimethyl sulfoxide (KOH-DMSO) and with chlorazol black E (KOH-CBE), interpreted by a dermatologist; culture using dermatophyte test medium, culture with Mycobiotic and Inhibitory Mold Agar (Cx); and histopathologic analysis using periodic acid-Schiff stain (PAS). This was a repeated-measure, blinded, cross-sectional study conducted at the Minneapolis Veterans Affairs Medical Center. Inclusion criteria included: at least one toenail with 25% or more clinical disease, which was defined as subungual debris with onycholysis and/or onychauxis. Exclusion criteria included other nail dystrophies, use of oral antifungal medication for 2 months or longer within the past year, or topical ciclopirox lacquer within 6 weeks of enrollment. The main outcome measure was the cost-effectiveness (Medicare and non-Medicare costs) of 7 diagnostic tests. Sensitivity (at least 3 positive tests) was the unit of effectiveness. Two hundred four participants were enrolled; their average age was 69.5 years and 95.5% were male. PAS was the most sensitive test (98.8%); it was statistically significantly more sensitive than all other diagnostic tests except KOH-CBE (94.3%). Dermatophye test medium was the least sensitive test (57.3%). KOH-CBE was statistically significantly more cost effective than any other test, with the exception of KOH-CLINIC and KOH-LAB. PAS was the least cost effective. Test specificities were not evaluated. KOH-CBE should be the test of choice for practitioners confident in interpreting KOH preparations because of its combination of high sensitivity and cost-effectiveness.